RPE Signaling in Ocular Health and Disease

眼部健康和疾病中的 RPE 信号传导

• 批准号: 10250509
• 负责人: Brian A Link
• 金额: $ 44.01万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10250509
• 关键词: Address; Animal Model; Animals; Basic Science; Binding Proteins; Blood Vessels; C-terminal; Cell Lineage; Cell physiology; Cells; Ciliary epithelium; Clinical; Cysteine; Defect; Disease; Epithelial Cells; Extracellular Matrix; Eye; Eye Abnormalities; Fibrosis; Frizzled Domain; Functional disorder; Genes; Glaucoma; Growth; Health; Homeostasis; Hyperopia; Immune response; Inflammation; Innate Immune Response; Integral Membrane Protein; LDL-Receptor Related Proteins; Lead; Link; Macrophage Activation; Maintenance; Microglia; Morphology; Mus; Mutate; Mutation; Myelogenous; Myopia; Names; Nerve Degeneration; Ocular Pathology; Pathogenesis; Pathology; Pathway interactions; Phenotype; Plant Roots; Protein Family; Proteins; Refractive Errors; Regulation; Research; Retina; Retinal Diseases; Retinal Dystrophy; Risk Factors; Role; Sclera; Signal Pathway; Signal Transduction; Signaling Protein; Testing; Zebrafish; experimental study; extracellular; genetic testing; human model; insight; macrophage; mutant; photoreceptor degeneration; recruit

RESEARCH SUMMARY This proposal describes experiments to address cellular functions of two transmembrane proteins, LRP2 and MFRP, that when mutated in humans and animal models cause a spectrum of ocular pathologies, including retinal dystrophies and refractive errors. LRP2 is a large transmembrane protein of the LDL- receptor related protein (LRP) family. MFRP is also a transmembrane protein and was named for its C- terminal and extracellular cysteine rich Frizzled domain, although it also has CUB and LDLA domains. Within eyes, both LRP2 and MFRP are specifically expressed on RPE and ciliary epithelial cells. Through three Specific Aims, we probe (1) the potential functional cooperatively between LRP2 and MFRP in receiving and transducing signals and regulating cellular processes (2) their involvement in recruitment and activation of macrophages in normal eye growth and during pathology, and (3) their protein binding partners and the possibility they interact directly. The proposed research will provide fundamental insights into regulation of specific signaling pathways and cellular processes of RPE cells with emphasis on their role in extracellular matrix homeostasis and in regulation of microglia and macrophages during ocular health and disease. Broadly, our studies will also help understand the links between ocular fibrosis and retinal pathologies.

研究综述 该提案描述了解决两种跨膜蛋白LRP 2的细胞功能的实验。 和MFRP，当其在人类和动物模型中突变时引起一系列眼部病理， 包括视网膜营养不良和屈光不正。LRP 2是LDL的一种大的跨膜蛋白。 受体相关蛋白（LRP）家族。MFRP也是一种跨膜蛋白，因其C- 末端和细胞外富含半胱氨酸的卷曲结构域，尽管它也具有CUB和LDLA结构域。 在眼睛内，LRP 2和MFRP都在RPE和睫状上皮细胞上特异性表达。通过 本研究从三个方面探讨了：（1）LRP 2与MFRP之间的潜在功能协同作用， 接收和传导信号并调节细胞过程（2）它们参与招募， 在正常眼生长和病理过程中激活巨噬细胞，和（3）它们的蛋白结合 合作伙伴和他们直接互动的可能性。拟议的研究将提供基本的见解 研究RPE细胞的特定信号通路和细胞过程的调节，重点是它们的 在细胞外基质稳态和调节小胶质细胞和巨噬细胞中的作用 健康和疾病。广泛地说，我们的研究也将有助于了解眼纤维化和 视网膜病变